Plant sterols as selective DNA polymerase β lyase inhibitors and potentiators of bleomycin cytotoxicity

In a survey of crude plant extracts for DNA polymerase β lyase inhibitors, the hexanes extracts of Cladogynus orientalis, Hymenache donacifolia, and Heteropsis integerrima, and the methyl ethyl ketone extract of Acacia pilispina were found to exhibit good inhibition of the dRP lyase activity of DNA polymerase β. Bioassay-guided fractionation of these extracts led to the isolation of three DNA polymerase β lyase inhibitory phytosterols, namely stigmasterol (1) and β-sitosterol (2), isolated from the hexanes extracts, and β-sitosterol-β-D-glucoside (3), isolated from the methyl ethyl ketone extract. Compounds 1-3 inhibited the DNA polymerase β lyase activity with IC₅₀ values of 43.6, 43.3, and 72.4μM, respectively. Compounds 1 and 2 were found capable of potentiating the action of bleomycin in cultured human tumor cells, consistent with the possibility that lyase inhibitors may find utility in vivo.